Developmental toxicity associated with receptor tyrosine kinase Ret inhibition in reproductive toxicity testing.

BACKGROUND: Urogenital abnormalities are among the most common of all human birth defects. In developmental toxicity studies with the Syk kinase inhibitor R788, a spectrum of findings, including renal agenesis, were observed. R788 has also been found to inhibit the receptor tyrosine kinase Ret. Ret kinase is known to be an essential component in the signaling pathway required for renal organogenesis and ureteric duct formation. Previously known is that mutant mice without the c-ret gene, develop urogenital malformations including renal agenesis. METHODS: In GLP developmental toxicity studies, gravid rabbits were treated orally with R788 at doses of 0, 10, 22, and 50 mg/kg/day (gestation days 7-19) and gravid rats received 0, 5, 12.5, and 25 mg/kg/day (gestation days 6-17) by the same route. The activity of R406 against Ret kinase was assessed in biochemical and cell-based assays. RESULTS: A dose-dependent increase in malformations, including renal and ureteric agenesis and a specific major vessel anomaly, retroesophageal right subclavian artery, was observed in both the rat and rabbit. R788 proved to be a potent inhibitor of Ret kinase. CONCLUSIONS: R788 promoted a spectrum of developmental toxicity, including renal and ureteric agenesis and a specific major vessel abnormality, retroesophageal right subclavian artery, in two different species. These effects are likely the result of inhibition of Ret kinase given its importance in the normal ontogeny of the urogenital and cardiovascular systems across species.

Percutaneous toxicokinetic and repeated cutaneous contact studies with ethylene glycol monohexyl ether.

Ethylene glycol monohexyl ether (EGHE; CAS no. 112-54-4) is a liquid industrial chemical with a potential for skin contact. The toxicokinetics of EGHE was investigated in Fischer 344 rats and New Zealand White rabbits by intravenous (i.v.) and 48-h occluded epicutaneous dosing. Given i.v. to male rats (2.5-25 mg kg(-1)) [(14)C]EGHE demonstrated fi rst-order kinetics. Carbon-14 was eliminated mainly in urine (68-74%) as metabolites, with no free EGHE. The plasma free EGHE concentration declined rapidly post-dosing and was not detectable by 8 h. Similar results were obtained for [(14)C]EGHE given i.v. to male rabbits in the dosage range 1-10 mg kg(-1), except that the metabolism of EGHE was more rapid, with no free EGHE being detectable in plasma by 1 h post-dosing. After cutaneous dosing of male and female rats with 25 mg kg(-1), there was rapid percutaneous absorption, with >95% of the radiochemical dose being recovered. Percutaneous bioavailability was >75%. Carbon-14 was excreted in urine (21-33%) to a lesser extent than by the i.v. route, and (14)CO(2) and volatiles accounted for 15-18%. Carbon-14 recovery was low from tissues and organs (0.39-0.46%), with no preferential accumulation. Extensive metabolism was indicated by the rapid decline in plasma free EGHE, with none being detectable by 48 h. Free EGHE was not present in urine, and urinary radioactivity was associated with up to seven metabolites. After cutaneous dosing of male and female rabbits (10 mg kg(-1)) ca. 75% of the dose was recovered, most (14)C being in urine (58-60%). Urine radioactivity was associated with up to nine metabolite peaks, but no free EGHE. The toxicokinetic findings indicate a significant percutaneous absorption of EGHE across both rat and rabbit skin, which is rapidly and extensively metabolized, with renal excretion being the principal route of elimination of metabolites. A 9-day repeated skin contact study in the male and female New Zealand White rabbit, using a dosage range of 44-444 mg kg(-1) day(-1), did not show any evidence for percutaneous systemic toxicity.